König Rainer, Kolte Amol, Ahlers Olaf, Oswald Marcus, Krauss Veiko, Roell Daniela, Sommerfeld Oliver, Dimopoulos George, Tsangaris Iraklis, Antoniadou Eleni, Jaishankar Neeraja, Bogatsch Holger, Löffler Markus, Rödel Markus, Garcia-Moreno Marina, Tuchscherr Lorena, Sprung Charles L, Singer Mervyn, Brunkhorst Frank, Oppert Michael, Gerlach Herwig, Claus Ralf A, Coldewey Sina M, Briegel Josef, Giamarellos-Bourboulis Evangelos J, Keh Didier, Bauer Michael
Integrated Research and Treatment Center, Center for Sepsis Control and Care, Jena University Hospital, Jena, Germany.
Institute of Infectious Diseases and Infection Control, Jena University Hospital, Jena, Germany.
Front Immunol. 2021 Mar 9;12:607217. doi: 10.3389/fimmu.2021.607217. eCollection 2021.
Large clinical trials testing hydrocortisone therapy in septic shock have produced conflicting results. Subgroups may benefit of hydrocortisone treatment depending on their individual immune response. We performed an exploratory analysis of the database from the international randomized controlled clinical trial Corticosteroid Therapy of Septic Shock (CORTICUS) employing machine learning to a panel of 137 variables collected from the Berlin subcohort comprising 83 patients including demographic and clinical measures, organ failure scores, leukocyte counts and levels of circulating cytokines. The identified theranostic marker was validated against data from a cohort of the Hellenic Sepsis Study Group (HSSG) ( = 246), patients enrolled in the clinical trial of Sodium Selenite and Procalcitonin Guided Antimicrobial Therapy in Severe Sepsis (SISPCT, = 118), and another, smaller clinical trial (Crossover study, = 20). In addition, blood culture experiments and experiments in mouse models were performed to assess biological plausibility. A low serum IFNγ/IL10 ratio predicted increased survival in the hydrocortisone group whereas a high ratio predicted better survival in the placebo group. Using this marker for a decision rule, we applied it to three validation sets and observed the same trend. Experimental studies revealed that IFNγ/IL10 was negatively associated with the load of (heat inactivated) pathogens in spiked human blood and in septic mouse models. Accordingly, an analysis of published IFNγ and IL10 values in bacteremic and non-bacteremic patients with the Systemic Inflammatory Response Syndrome supported this association between the ratio and pathogen burden. We propose IFNγ/IL10 as a molecular marker supporting the decision to administer hydrocortisone to patients in septic shock. Prospective clinical studies are necessary and standard operating procedures need to be implemented, particularly to define a generic threshold. If confirmed, IFNγ/IL10 may become a suitable theranostic marker for an urging clinical need.
在感染性休克中测试氢化可的松疗法的大型临床试验产生了相互矛盾的结果。根据个体免疫反应，亚组可能从氢化可的松治疗中获益。我们对国际随机对照临床试验“感染性休克的皮质类固醇治疗（CORTICUS）”的数据库进行了探索性分析，采用机器学习方法分析从柏林亚组收集的137个变量，该亚组包括83名患者，变量涵盖人口统计学和临床指标、器官衰竭评分、白细胞计数以及循环细胞因子水平。所确定的治疗诊断标志物在希腊脓毒症研究组（HSSG）队列（n = 246）、参加亚硒酸钠和降钙素原指导的严重脓毒症抗菌治疗临床试验（SISPCT，n = 118）的患者以及另一项较小的临床试验（交叉研究，n = 20）的数据中得到验证。此外，还进行了血培养实验和小鼠模型实验以评估生物学合理性。低血清IFNγ/IL10比值预示氢化可的松组生存率提高，而高比值则预示安慰剂组生存率更佳。将该标志物用作决策规则，应用于三个验证集并观察到相同趋势。实验研究表明，IFNγ/IL10与加样人血和感染性小鼠模型中（热灭活）病原体载量呈负相关。相应地，对全身炎症反应综合征的菌血症和非菌血症患者中已发表的IFNγ和IL10值进行的分析支持了该比值与病原体负荷之间的这种关联。我们提出IFNγ/IL10作为一种分子标志物，支持对感染性休克患者使用氢化可的松的决策。前瞻性临床研究是必要的，并且需要实施标准操作程序，特别是要确定一个通用阈值。如果得到证实，IFNγ/IL10可能成为满足迫切临床需求的合适治疗诊断标志物。
